Genetic downregulation of pregnancy-associated plasma protein-A (PAPP-A) by bikunin reduces IGF-I-dependent Akt and ERK1/2 activation and subsequently reduces ovarian cancer cell growth, invasion and metastasis.

Abstract

A Kunitz-type protease inhibitor, bikunin, downregulates expression of uPA and its receptor uPAR at the mRNA and protein levels in several types of tumor cells. Our recent work showed that, using a cDNA microarray analysis, pregnancy-associated plasma protein-A (PAPP-A) is a candidate bikunin target gene. To clarify how reduced levels of PAPP-A may confer repressed invasiveness, we transfected human ovarian cancer cell line HRA with antisense (AS)-PAPP-A cDNA and compared the properties of the transfected cells to those of parental HRA cells. Here, we show that regulation of uPA mRNA and protein by IGF-I depends on the PI3K and MAPK signaling pathways and phosphorylation of Akt and ERK1/2 is required for IGF-I-mediated cell invasion; that IGFBP-4 protease in HRA cells is identified as PAPP-A; that reduced PAPP-A expression is associated with the upregulation of IGFBP-4 expression; that higher intact IGFBP-4 levels were associated with low invasive potential and growth rate in AS-PAPP-A cells in response to IGF-I; that IGF-I stimulates Akt and ERK1/2 activation of both the control and antisense cells, but the relative potency and efficacy of IGF-I were lower in the antisense cells compared to the control; and that genetic downregulation of PAPP-A reduces the proliferation, invasion and metastasis of HRA cells. In conclusion, our data identify a novel role for PAPP-A as a bikunin target gene. IGF-I-induced IGFBP-4 proteolysis by PAPP-A may enhance cell growth and invasion through IGF-I-dependent Akt and ERK1/2 activation and subsequently upregulation of uPA.

• Authors: Yoshiko Tanaka, Hiroshi Kobayashi, Mika Suzuki, Yasuyuki Hirashima, Naohiro Kanayama, Toshihiko Terao
• Journal: International journal of cancer (Int J Cancer) Vol. 109 Issue 3 Pg. 336-47 (Apr 10 2004) ISSN: 0020-7136 [Print] United States
• PMID: 14961570 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2004 Wiley-Liss, Inc.

Chemical References

• Insulin-Like Growth Factor Binding Protein 4
• Membrane Glycoproteins
• Oligonucleotides, Antisense
• Proto-Oncogene Proteins
• RNA, Messenger
• SPINT2 protein, human
• Serine Proteinase Inhibitors
• Insulin-Like Growth Factor I
• Trypsin Inhibitor, Kunitz Soybean
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Urokinase-Type Plasminogen Activator
• Pregnancy-Associated Plasma Protein-A

Topics

• Cell Division (drug effects)
• Down-Regulation (drug effects)
• Enzyme Activation
• Female
• Humans
• Insulin-Like Growth Factor Binding Protein 4 (metabolism)
• Insulin-Like Growth Factor I (pharmacology)
• MAP Kinase Signaling System
• Membrane Glycoproteins (pharmacology)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (metabolism)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Oligonucleotides, Antisense (pharmacology)
• Ovarian Neoplasms (metabolism, pathology)
• Pregnancy-Associated Plasma Protein-A (genetics, metabolism)
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• RNA, Messenger (metabolism)
• Serine Proteinase Inhibitors (pharmacology)
• Trypsin Inhibitor, Kunitz Soybean (pharmacology)
• Tumor Cells, Cultured
• Urokinase-Type Plasminogen Activator (genetics)